Pharmaceutical compositions of neurokinin receptor antagonists and cyclodextrin and methods for improved injection site toleration

ABSTRACT

This invention relates to pharmaceutical compositions for improving anesthesia recovery and preventing nausea and emesis and a method for improved injection site tolerance. In particular, the invention is directed to pharmaceutical compositions with an improved injection site toleration comprising an effective amount of a neurokinin receptor antagonist with a pharmaceutically acceptable cyclodextrin. The invention is also directed to pharmaceutical compositions of the compound of Formula (I), wherein R 2  is selected from the group consisting of methyl, ethyl, isopropyl, sec-butyl and tert-butyl. The invention is also directed to pharmaceutical compositions of the compound of Formula Ia, and cyclodextrins and methods for improved injection site toleration thereof.

FIELD OF INVENTION

The present invention is directed to pharmaceutical compositionscontaining cyclodextrins for improved injection site toleration andneurokinin receptor (NK-1) antagonists. The invention is also directedto pharmaceutical compositions of the compounds of Formula I, wherein R²is selected from the group consisting of methyl, ethyl, isopropyl,sec-butyl and tert-butyl.

In particular, the invention is directed to pharmaceutical compositionsof the compound of Formula Ia,(2S,3S)-2-benzhydryl-N-(5-tert-butyl-2-methoxybenzyl)quinuclidin-3-amine,and cyclodextrins for improved injection site toleration.

BACKGROUND OF THE INVENTION

The compounds of Formula I or Ia are the subject of U.S. Pat. No.5,807,867, U.S. U.S. Pat. No. 6,222,038 and U.S. Pat. No. 6,255,320. Thepreparation of compounds of Formula I and Ia are described therein. Thecompound of Ia may also be prepared as described in the co-pending U.S.provisional application No. 60/541,323, commonly owned and assigned toPfizer, Inc. U.S. Pat. No. 5,393,762 also describes pharmaceuticalcompositions and treatment of emesis using NK-1 receptor antagonists.Co-pending U.S. provisional application No. 60/540,697, commonly ownedand assigned to Pfizer, Inc., described a method of improving anesthesiarecovery in patients by administering the compound of Formula Ia or Ia.The text of the aforementioned applications, patents and all otherreferences cited in this specification are hereby incorporated byreference in their entirety.

Prevention and/or treatment of emesis has focused on substances thatblock or hinder neurokinin receptor (NK-1) activity. These substancesare known as neurokinin receptor antagonists. There are numerousneurokinin receptor antagonists known in the art. Neurokinin antagonistsinclude, but are not limited to, piperizino derivatives (U.S. Pat. No.5,798,359), trypthophan urea (U.S. Pat. No. 5,869,489),spiro-substituted azacycles (U.S. Pat. No. 5,869,496), various aminoacid derivatives (U.S. Pat. No. 5,849,918), arylglycinamide derivatives(U.S. Pat. No. 6,124,296), therapeutic heterocycles (U.S. Pat. No.6,124,279), aromatic amine compounds (U.S. Pat. No. 5,686,609),quaternary imodium salts (U.S. Pat. No. 5,674,881), and other neurokininreceptor antagonists known to those of skill in the art.

Administering NK-1 antagonists, however, present various problems withregard to injection site tolerance (e.g., irritability of subject,irritation, inflammation, swelling, and/or redness of the site).Although there have been numerous studies with regard to improvinginjection site tolerance through the use of various substances, none ofthese studies, however, have focused on neurokinin receptor antagonistadministration.

It was determined that improved injection site toleration was realizedby the addition of a cyclodextrin to the pharmaceutical compositioncontaining a neurokinin receptor antagonist. Cyclodextrins are cyclicoligosaccharides. There are three main cyclodextrins: α-cyclodextrin iscomposed of a ring of six glucose residues; β-cyclodextrin is composedof a ring of seven glucose residues; and γ-cyclodextrin is composed of aring of eight glucose residues. Typically, cyclodextrins are formed bythe action of an amylase on starch. Cyclodextrins typically vary inshape and size, but are, generally, defined by the presence of ahydrophobic cavity and can form inclusion compounds with other organicmolecules, with salts, and with halogens either in solid state or inaqueous solution. Methods for preparing cyclodextrins are well known tothose of skill in the art and many cyclodextrins are commerciallyavailable.

Cyclodextrins have been utilized in attempts to improve injection sitetolerance. For example, WO/0062793 to Vasudevan, et al. disclosesmethods and compositions for treating fungal infections that includeformulations of a pseudomycin or related anti-fungal agent and acyclodextrin. U.S. Pat. No. 6,048,845 to Rubinfeld disclosescompositions of matter including a substituted cyclodextrin andcytotoxic compound. U.S. Pat. No. 5,024,998 to Bodor discloses aqueousparenteral solutions of drugs that are insoluble or only sparinglysoluble in water and/or that are unstable in water, combined withhydroxypropyl-62 -cyclodextrin.

Accordingly, there is a need for a composition and method for improvinginjection site tolerance of a pharmaceutical formulation in thetreatment of emesis or improving anesthesia recovery in a subjectpatient. Further, there is a need for a composition and/or medicamentthat has improved injection site tolerance for the administration ofneurokinin receptor antagonists. Additionally, there is a need for amethod of improving injection site tolerance and preventing nausea andemesis and improving anesthesia recovery through the use of a NK-1antagonist.

SUMMARY OF INVENTION

In one aspect, the invention is directed to a pharmaceutical compositionwith an improved injection site toleration comprising an effectiveamount of a neurokinin receptor (NK-1) antagonist, such as thosedescribed in the references cited herein, with a pharmaceuticallyacceptable cyclodextrin. Further neurokinin receptors are disclosed inU.S. Pat. No. 5,807,867, U.S. Pat. No. 6,222,038, U.S. Pat. No.6,255,320, U.S. Pat. No. 5,939,433 and U.S. Pat. No. 5,519,033, whichare hereby incorporated by reference for all purposes.

In a preferred embodiment, the antagonist is selected from the groupconsisting of piperazine compounds, spiro-substituted azacycles,dialkyline piperadino compounds, trypthophan urea, polycyclic aminecompounds, substituted arylaliphatic compounds, aromatic aminecompounds, quaternary ammonium salts or aromatic amine compounds,aryl-substituted heterocycles, polycyclicamine compounds, substitutedaryl piperazines, carboxamide derivatives, bis-piperadinyl non-peptidalcompounds, salts thereof, and(2S,3S)-2-benzhydryl-N-(5-tert-butyl-2-methoxybenzyl)quinuclidin-3-amine.

In a more preferred embodiment, the antagonist is the compound ofFormula Ia,(2S,3S)-2-benzhydryl-N-(5-tert-butyl-2-methoxybenzyl)quinuclidin-3-amine,or a pharmaceutically acceptable salt thereof, preferably the citratesalt, such as the citrate monohydrate salt.

In one embodiment, the cyclodextrin is selected from a pharmaceuticallyacceptable β-cyclodextrin, hydroxypropyl β-cyclodextrin, sulfobutyletherβ-cyclodextrin (“SBE-CD”) or substituted cyclodextrins. In anotherembodiment, the cyclodextrin is about 2% to about 40% of the vehicle byweight. Preferentially, the cyclodextrin is about 4% to about 20% of thecomposition. More preferably, the cyclodextrin is about 5% to about 10%of the composition and is hydroxypropyl β-cyclodextrin or SBE-CD.

In a preferred embodiment, the therapeutically effective amount of theNK-1 antagonist is about 0.01 mg/kg to about 100 mg/kg of a patient'sbody weight. More preferably the therapeutically effective amount isabout 0.10 mg/kg to about 10 mg/kg.

In another aspect, the invention is directed to a method for thetreatment of emesis or improving anesthesia recovery in a mammal using aNK-1 receptor antagonist comprising parenterally injecting into themammal an aqueous pharmaceutical solution comprising the pharmaceuticalcomposition described above in a therapeutically effective amountsufficient for treating emesis, the cyclodextrin being present inamounts that are sufficient for improving injection toleration at theinjection site.

In another aspect, the invention is directed to a method for improvinginjection site toleration during the treatment of emesis or improvinganesthesia recovery in a mammal comprising parenterally injecting intothe mammal an aqueous pharmaceutical solution comprising thepharmaceutical composition described above.

In a further aspect, the invention is directed to a pharmaceuticalcomposition, as defined herein, for use as a medicament especially inthe treatment of a disease for which a NK-1 receptor antagonist isindicated.

In a further aspect, the invention is directed to the use of apharmaceutical composition, as defined herein, in the manufacture of amedicament for the treatment of a disease for which a NK-1 receptorantagonist is indicated.

In a further aspect, the invention is directed to a method for thetreatment of a disease for which a NK-1 receptor antagonist is indicatedin mammals comprising administering to said mammal a therapeuticallyeffective amount of a pharmaceutical composition as defined herein.

DEFINITIONS

The term(s) “compound(s) of Formula I,” “compound of Formula Ia” and“compound(s) of this invention” as used herein, means a compound orcompounds of Formula I or Ia, prodrugs thereof and pharmaceuticallyacceptable salts of the compounds or the prodrugs. The term“compound(s),” when referring to compounds of Formula Ia, also includesprodrugs of the compound(s) and pharmaceutically acceptable salts of thecompound(s) or the prodrugs.

In an embodiment of any of the compositions or methods of the invention,the pharmaceutically acceptable acid may be selected from the groupconsisting of acetic acid, benzenesulfonic acid, citric acid,hydrobromic acid, hydrochloric acid, D- and L-lactic acid,methanesulfonic acid, phosphoric acid, succinic acid, sulfuric acid, D-and L-tartaric acid, p-toluenesulfonic acid, adipic acid, aspartic acid,camphorsulfonic acid, 1,2-ethanedisulfonic acid, laurylsulfuric acid,glucoheptonic acid, gluconic acid, 3-hydroxy-2-naphthoic acid,1-hydroxy-2-naphthoic acid, 2-hydroxyethanesulfonic acid, malic acid,mucic acid, nitric acid, naphthalenesulfonic acid, palmitic acid,D-glucaric acid, stearic acid, maleic acid, malonic acid, fumaric acid,benzoic acid, cholic acid, ethanesulfonic acid, glucuronic acid,glutamic acid, hippuric acid, lactobionic acid, lysinic acid, mandelicacid, napadisylic acid, nicotinic acid, polygalacturonic acid, salicylicacid, sulfosalicylic acid, tryptophanic acid, and mixtures thereof. In apreferred embodiment thereof, the acid is citric acid.

The term “citrate salt,” as used herein, refers to the citratemonohydrate salt of the compound of Formula Ia, having a molecularweight of 660.82 and a theoretical potency based on the activeingredient of 709 mg/g.

The term “neurokinin receptor antagonist” as used herein includes, butis not limited to, compounds of Formula I or Ia or various ligands,compounds, and/or substances that can specifically bind to the NK-1neurokinin receptors and includes, but are not limited to, piperazinecompounds, spiro-substituted azacycles, dialkyline piperadino compounds,trypthophan urea, polycyclic amine compounds, substituted arylaliphaticcompounds, aromatic amine compounds, quaternary ammonium salts oraromatic amine compounds, aryl substituted hetrocycles, polycyclicaminecompounds, substituted aryl piperazines, carboxamide derivatives,bis-piperadinyl non-peptidal compounds, salts thereof, and any othersimilar neurokinin receptor antagonist known to those of skill in theart. Further neurokinin receptors are those disclosed in U.S. Pat. No.5,807,867, U.S. Pat. No. 6,222,038, U.S. Pat. No. 6,255,320, U.S. Pat.No. 5,939,433 and U.S. Pat. No. 5,519,033 and are included in the abovedefinition.

The term “cyclodextrin” as used herein means a cyclic oligosaccharidehaving a hydrophobic interior cavity and a hydrophilic exterior. Thereare three main types of cyclodextrins: α-cyclodextrin, β-cyclodextrinand γ-cyclodextrin. The term “cyclodextrin” also includes varioussubstituted cyclodextrins, including as side chains any organic moietyor a heteroorganic moiety. Substituted cyclodextrins also includecyclodextrins that have been alkylated, hydroxyalkylated, or reacted toform a sulfoalkyl ether.

As used herein, cyclodextrins and/or substituted cyclodextrins include,but are not limited to, sulfobutylether cyclodextrin, hydroxypropylcyclodextrin, hydroxyethyl cyclodextrin, glucosyl cyclodextrin, maltosylcyclodextrin, hydroxypropyl-β-cyclodextrin,sulfobutylether-β-cyclodextrin, hydroxyethyl-β-cyclodextrin,hydroxypropyl-γ-cyclodextrin, hydroxyethyl-β-cyclodextrin,dihydroxypropyl-β-cyclodextrin, glucosyl-β-cyclodextrin,diglycosyl-β-cyclodextrin, maltosyl-β-cyclodextrin,maltosyl-γ-cyclodextrin, maltotrialsyl-β-cyclodextrin,maltotrialsyl-γ-cyclodextrin, dimaltosyl-β-cyclodextrin, cyclodextrinderivatives, various mixtures of cyclodextrin derivatives thereof,mixtures such as maltosyl-β-cyclodextrin/dimaltosyl-β-cyclodextrin, andany other similar cyclodextrin known to those of skill in the art.

The term “pharmaceutically acceptable diluent” is meant to refer todiluents or vehicles, or mixtures thereof, acceptable for parenteralapplications in both human and veterinary fields and includes water orother pharmaceutically acceptable excipients for use in making thecompositions of the invention (including but not limited to e.g. waterfor injection, water, water miscible organic solvents, propylene glycol,2-pyrrolidone, ethanol, n-methyl pyrrolidone, polyethylene glycol,glycerol formal, oily vehicles, sesame oil, safflower oil and the like)

The term “improved injection site toleration” as used herein means ascore of two or less, preferably, one or less, in each of the signs ofreaction as defined herein in Table 1.

The term “active ingredient” or “mgA/mL”, as used herein, refers to thefree base of the compound of Formula Ia, having a molecular weight of468.69.

The phrase “therapeutically effective amount” means an amount of acompound of the present invention that (i) treats or prevents theparticular disease, condition or disorder, (ii) attenuates, amelioratesor eliminates one or more symptoms of the particular disease, conditionor disorder, or (iii) prevents or delays the onset of one or moresymptoms of the particular disease, condition or disorder describedherein.

The phrase “pharmaceutically acceptable” indicates that the substance orcomposition must be compatible chemically and/or toxicologically, withthe other ingredients comprising a formulation, and/or the mammal beingtreated therewith.

The terms “treating”, “treat” or “treatment” embrace both palliative andpreventative (i.e. prophylactic) treatment.

DESCRIPTION OF INVENTION

The compounds of Formula I or Ia can be prepared as described in U.S.Pat. No. 6,222,038 or U.S. Pat. No. 6,255,038. Salts of the compound ofFormula Ia, in particular the citrate salt, can be prepared as describedin the above patents or as briefly described below.

For example, the crystalline citrate monohydrate salt of the compound ofFormula Ia was prepared by suspending 47 grams of the free base in 470mL of isopropyl ether under ambient conditions. To the slurry was added21.42 grams anhydrous citric acid at room temperature. The mixture wasconverted to the monohydrate by suspending in 150 mL of water foreighteen hours and filtered, providing a white crystalline solid.

With respect to the present invention, formulations are prepared bydissolving a therapeutically effective amount of the compounds ofFormula I or Ia in a pharmaceutically acceptable diluent. Apharmaceutically acceptable salt of the compound of Formula Ia may alsobe used, such as the citrate or malate salts. A cyclodextrin is added tothe solution in a concentration range of about 2% to about 40%.Preferably, the cyclodextrin comprises about 4% to about 20% of thepharmaceutical composition and more preferably about 5% to about 10%.Preferably, the cyclodextrin is a β-cyclodextrin: hydroxypropylβ-cyclodextrin, sulfobutylether β-cyclodextrin or other pharmaceuticallyacceptable substituted β-cyclodextrin.

As used herein, a “therapeutically effective amount” for a dosage unitmay typically be about 0.5 mg to about 500 mg of active ingredient. Thedose may vary, however, depending on the species, variety, etc. ofanimal to be treated, the severity and the body weight of the animal.Accordingly, based upon body weight, typical dose ranges of the activeingredient may be from about 0.01 to about 100 mg per kg of body weightof the animal. Preferably, the range is from about 0.10 mg to about 10mg per kg of body weight.

The veterinary practitioner, or one skilled in the art, will be able todetermine the dosage suitable for the particular individual patient,which may vary with the species, age, weight and response of theparticular patient. The above dosages are exemplary of the average case.Accordingly, higher or lower dosage ranges may be warranted, dependingupon the above factors, and are within the scope of this invention.

Pharmaceutical compositions of the compounds of Formula I or Ia weredeveloped such that a therapeutically effective amount of the compoundsof Formula I or Ia could be administered to a patient with an acceptableinjection site toleration. Injection site toleration was measured byinspecting the patient for signs of reaction, including erythema (size),skin thickening (size), pain on palpation and edema. Table 1 provides adetailed explanation of the scoring system: a score of 0 (no reaction)to 4 (severe reaction) was given for each characteristic and eachinjection site daily. TABLE 1 Explanation of Scoring Systems Used forSubcutaneous Injection Site Toleration Signs of Reaction Pain on TissuePain on Score Injection Erythema Thickening Palpation Edema 0 noresponse no erythema no no pain no edema thickening 1 very slight Veryslight very slight Mild pain very mild response; erythema; reaction; ondeep edema; hunch, look at barely barely palpation barely siteperceptible perceptible perceptible 2 mild response; Mild erythema;mild, Mild pain mild minor well defined palpable on palpablevocalization; reaction; ≦1 palpation edema lick/scratch at cm site 3moderate Moderate moderate, moderate moderate response major erythemapalpable pain on palpable vocalization; reaction palpation focal bite atsite, 1-2 cm edema motor activity 4 severe Severe severe severe severeresponse erythema reaction; >2 pain on diffuse similar to 3; >5 beetredness cm palpation edema min duration any eschar formation

The pharmaceutical compositions can further include a preservative toprevent microbial contamination, as more fully described in U.S.Provisional Application, contemporaneously filed, commonly owned andassigned to Pfizer, Inc. The above application is incorporated byreference in its entirety for all purposes. As used herein, the word“preservative” means a compound, or combination of compounds, added toprevent or inhibit the growth of microorganisms which could present arisk of infection or degradation of the medicinal product.

Any of the compositions and/or pharmaceutical compositions describedabove can be administered solely with the neurokinin receptor antagonistand the cyclodextrin. However, it is possible for additional ingredientsto be included within the composition or pharmaceutical composition.Further, various conventional carriers and excipients can be utilized inaccord with ordinary practice. Typically, the compositions and/orpharmaceutical compositions are aqueous formulations prepared in sterileform and are isotonic when delivered. Additional excipients include, butare not limited to, antioxidants, chelating agents such asethylenediaminetetraacetic acid (“EDTA”), carbohydrates, and any othersimilar ingredients known to those of skill in the art. Furthermore, theapparent pH of the formulations ranges from about three to about seven,but is ordinarily from about four to about six. With regard to thevarious carriers, any known pharmaceutically acceptable carrier, thatproperly solubilizes the NK-1 antagonist can be utilized with thepresent invention.

The compositions and pharmaceutical compositions of the presentinvention can be administered in a number of ways; most preferablyparenterally.

GENERAL EXPERIMENTAL PROCEDURES

Unless specified otherwise, commercial reagents were utilized withoutfurther purification and may be obtained from, for example, Sigma orAldrich. HPB-CD (Cavitron 82003) was obtained from Cargill. Ethyl oleate(Crodamol) was obtained from Croda Inc. Miglyol 812 (Nutralol) wasobtained from Condia.

Individual sodium chloride, calcium choride, and sodium acetate 1%solutions were prepared by dissolving 1 gram of the respective salt insufficient water for injection to provide a final volume of 100 mL. Oneskilled in the art would appreciate that alternate volumes of solutionmay be prepared by scaling the volume of the solution components asappropriate in relation to the amount of salt added.

Forty (40)% glycerol formal solutions were prepared by dispersing 40grams glycerol formal in sufficient water for injection to produce afinal volume of 100 mL.

The following Examples are intended to illustrate particular embodimentsof the invention and are not intended to limit the specification,including the claims in any manner.

EXAMPLE Injection Site Toleration Study of Compound of Formula Ia

The injection site toleration of compound of Formula Ia in variouspharmaceutically acceptable diluents was evaluated. The compound ofFormula Ia was administered by subcutaneous injection to beagle ormongrels dogs at 1 mg/kg/day for one to four consecutive days. Dogs wereobserved immediately following each dose for evidence of pain oninjection. All injection sites were evaluated daily until at leasttwenty-four hours after the last injection for evidence of reaction.

The following formulations utilized in the injection site tolerationstudy were prepared as described below. The formulations provide thefinal concentration of the active ingredient, the compound of FormulaIa, prepared from the citrate salt of the compound of Formula Ia, havingan actual potency of 692 mg/g, unless designated otherwise.

The formulation solutions were filtered through a 0.22 micron MilliporeGV filter membrane into sterilized 30 mL vial(s) closed with a rubberstopper, except for Examples Y, Z, AA, BB, CC, DD, EE and II that werefiltered through a 0.45 micron Millipore HV filter membrane into asterilized 20 mL vial(s) closed with a rubber stopper.

For those Examples having sulfobutylether β-cyclodextrin (“SBE-CD”) aspart of the pharmaceutical composition, the sodium salt of SBE-CD wasutilized.

Example A 1% Sodium Chloride; 10 mg/mL Compound of Formula Ia

A 10 mg/mL solution of compound of Formula Ia was prepared by dissolving0.51 grams of the citrate salt of the Compound of Formula Ia in 34.49grams of a 1% sodium chloride solution, providing approximately 35 mL ofsolution with a pH of 3.89.

Example B 1% Calcium Chloride; 10 mg/mL Compound of Formula Ia

A 10 mg/mL solution of compound of Formula Ia was prepared by dissolving0.51 grams of the citrate salt of the compound of Formula Ia in 34.51grams of a 1% calcium chloride solution, providing approximately 35 mLof solution with a pH of 3.45.

Example C 1% Sodium Acetate; 10 mg/mL Compound of Formula Ia

A 10 mg/mL solution of compound of Formula Ia was prepared by dissolving0.51 grams of the citrate salt of the compound of Formula Ia in 34.51grams of a 1% sodium acetate solution, providing approximately 35 mL ofsolution with a pH of 5.24.

Example D 40% Glycerol Formal; 10 mg/mL Compound of Formula Ia

A 10 mg/mL solution of compound of Formula Ia was prepared by dissolving0.51 grams of the citrate salt of the compound of Formula Ia in 37.78grams of a 40% glycerol formal solution, providing approximately 35 mLof solution with an apparent pH of 4.55.

Example E 25% 2-pyrrolidone; 10 mg/mL Compound of Formula Ia

A 10 mg/mL solution of compound of Formula Ia was prepared by adding0.51 grams of the citrate salt of the compound of Formula Ia to 36.30grams of a 25% 2-pyrrolidone solution (25 grams 2-pyrrolidone insufficient water for injection (78.27 grams) to make 100 mL ofsolution). To enhance dissolution of the compound of Formula Ia, 10%hydrochloric acid (“HCl”) (6.75 grams of concentrated HCl in sufficientwater for injection (18.24 grams) to give 25.00 grams of solution) wasadded in portions of 5, 5, 10, 10, 10, 50, and 50 μL for a total of 140μL, providing approximately 35 mL of solution with an apparent pH of4.05.

Example F 1% Calcium Chloride; 5 mg/mL Compound of Formula Ia

A 5 mg/mL solution of Compound of Formula Ia was prepared by dissolving0.51 grams of the citrate salt of Compound of Formula Ia in 69.49 gramsof a 1% calcium chloride solution, providing approximately 70 mL ofsolution with a pH of 3.54.

Example G 1% Calcium Chloride: 10 mg/mL Compound of Formula Ia

A 10 mg/mL solution of Compound of Formula Ia was prepared by dissolving0.51 grams of the citrate salt of Compound of Formula Ia in 34.50 gramsof a 1% calcium chloride solution, providing approximately 35 mL ofsolution with a pH of 3.45.

Example H 40% Glycerol Formal; 5 mg/mL Compound of Formula Ia

A 5 mg/mL solution of Compound of Formula Ia was prepared by dissolving0.51 grams of the citrate salt of compound of Formula Ia in 75.09 gramsof a 40% glycerol formal solution, providing approximately 70 mL ofsolution with an apparent pH of 4.64.

Example I 40% Glycerol Formal, 10 mg/mL Compound of Formula Ia

A 10 mg/mL solution of compound of Formula Ia was prepared by dissolving0.51 grams of the citrate salt of compound of Formula Ia in 37.29 gramsof a 40% glycerol formal solution, providing approximately 35 mL ofsolution with an apparent pH of 4.56.

Example J 20% SBE-CD; 10 mg/mL Compound of Formula Ia

A 10 mg/mL solution of compound of Formula Ia was prepared by dissolving1.45 grams of the citrate salt of the compound of Formula Ia insufficient 20% SBE-CD solution (20 grams of SBE-CD dissolved insufficient water for injection to produce volume of 100 mL).

Example K 1% Calcium Chloride; 10 mg/mL Compound of Formula Ia

A 10 mg/mL solution of compound of Formula Ia was prepared by dissolving0.51 grams of the citrate salt of Compound of Formula Ia in 33.89 gramsof a 1% calcium chloride/sodium hydroxide solution (0.52 grams of a 10%sodium hydroxide solution (2.50 grams of sodium hydroxide dissolved insufficient water for injection to make 25.00 grams of solution) wasadded to a 1% calcium chloride solution), providing approximately 35 mLof solution with a pH of 5.00.

Example L 1% Calcium Chloride; 10 mg/mL Compound of Formula Ia

A 10 mg/mL solution of compound of Formula Ia was prepared by dissolving0.45 grams of the malate salt of compound of Formula Ia (theoreticalpotency 780 mg/gram) in 34.58 grams of a 1% calcium chloride solution,providing approximately 35 mL of solution with a pH of 3.76.

Example M 40% Glycerol Formal/Phosphate Buffer; 10 mg/mL Compound ofFormula Ia

A 100 millimolar solution of sodium dihydrogen phosphate dihydrate(“NaH₂PO₄.2H₂O”) was prepared by dissolving 1.38 grams of NaH₂PO₄.2H₂Oin sufficient water for injection to make 100 mL of solution. A 100millimolar solution of phosphoric acid (“H₃PO₄”) was prepared bydispersing 1.13 grams 86.7% H₃PO₄ in sufficient water for injection tomake 100 mL of solution. A 100 millimolar pH 2.02 phosphate buffer wasprepared by combining 60 mL of the NaH₂PO₄.2H₂O solution whosepreparation is described above and 45 mL of the H₃PO₄ solution whosepreparation is described above. A 40% (weight/volume) solution ofglycerol formal in 50 millimolar phosphate buffer was prepared bydispersing 40.15 grams of glycerol formal in 49.0 grams of the 100millimolar, pH 2 phosphate buffer and sufficient water for injection(19.47 grams) to make 100 mL of solution. The apparent pH of theresulting solution was 2.61.

A 10 mg/mL solution of compound of Formula Ia was prepared by dissolving0.504 grams of the citrate salt of Compound of Formula Ia in 38.06 gramsof the 40% glycerol formal solution whose preparation is describedabove. The pH was adjusted by adding 10% HCl (13.5 grams of concentratedHCl in sufficient water for injection to give 50 grams of solution) inportions of 20, 50, 50, 40, and 20 μL for a total of 180 μL, providingapproximately 36 mL of solution with an apparent pH of 3.01.

Example N 25% N-methylpyrrolidone: 10 mg/mL Compound of Formula Ia

A 10 mg/mL solution of Compound of Formula Ia was prepared by adding0.510 grams of the citrate salt of compound of Formula Ia to 35.44 gramsof a 25% N-methylpyrrolidone (“NMP”) solution (12.51 grams ofN-methylpyrrolidone in sufficient water for injection (38.08 grams) tomake 50 mL of solution), providing approximately 36 mL of solution withan apparent pH of of 4.60.

Example O 1% Calcium Chloride: 10 mg/mL Compound of Formula Ia

A 10 mg/mL solution of compound of Formula Ia was prepared by dissolving0.35 grams of the free base of compound of Formula Ia (theoreticalpotency 1000 mg/gram) in 34.30 grams of a 1% calcium chloride solutionto which was added 0.30 grams of 10% HCl (13.5 grams of concentrated wasdispersed in sufficient water for injection to give 50 grams ofsolution), providing approximately 35 mL of solution with a pH of 4.10.

Example P 5% SBE-CD; 10 mg/mL Compound of Formula Ia

A 10 mg/mL solution of compound of Formula Ia was prepared by adding0.504 grams of the citrate salt of compound of Formula Ia to 35.60 gramsof a 5% SBE-CD solution (5.00 grams of the sodium salt of SBE-CDdissolved in sufficient water for injection (96.73 grams) to make 100mL), providing approximately 35 mL of solution with a pH of 4.46.

Example Q 5% SBE-CD/1% Calcium Chloride; 10 mg/mL Compound of Formula Ia

A solution containing 5% SBE-CD and 1% calcium chloride was prepared bydissolving 0.3 grams of calcium chloride in 30.7 grams of the 5% SBE-CD(preparation described above) to give approximately 30 mL of solution. A10 mg/mL solution of compound of Formula Ia was prepared by adding 0.44grams of the citrate salt of compound of Formula Ia to 30.7 grams of the5% SBE-CD/1% calcium chloride solution, providing approximately 31 mL ofsolution with a pH of 4.55.

Example R 30% PEG400; 10 mg/mL Compound of Formula Ia

A 10 mg/mL solution of compound of Formula Ia was prepared by dispersing2.67 grams of the citrate salt of compound of Formula Ia in 191.99 gramsof 30% polyethylene glycol 400 (“PEG-400”) solution (90.06 grams ofPEG400 in sufficient water for injection (223.17 grams) to make 300 mLof solution). The pH was adjusted by adding 10% HCl (13.5 grams ofconcentrated (37% weight/weight) HCl dispersed in sufficient water forinjection to give 50 grams of solution) in portions of 1.98 grams and0.407 grams for a total of 2.39 grams, providing approximately 189 mL offinal solution with an apparent pH of 2.97.

Example S 30% PG; 10 mg/mL Compound of Formula Ia

A 10 mg/mL solution of compound of Formula Ia was prepared by dispersing2.76 grams of the citrate salt of compound of Formula Ia in 193.33 gramsof a 30% propylene glycol (“PG”) solution (90.01 grams of PG dispersedin sufficient water for injection (218.53 grams) to make 300 mL ofsolution). The pH was adjusted by adding 10% HCl in portions of 1.88grams and 0.39 grams for a total of 2.27 grams, providing approximately193 mL of final solution with an apparent pH of 3.01.

Example T 1% Calcium Chloride; 10 mg/mL Compound of Formula Ia

A 10 mg/mL solution of compound of Formula Ia was prepared by dissolving0.35 grams of the free base of compound of Formula Ia (theoreticalpotency 1000 mg/grams) in 33.90 grams of a 1% calcium chloride solutionto which was added 0.76 grams of a 10% methanesulfonic acid solution (1gram of methanesulfonic acid and 9 grams of water for injection to give10 grams of solution), providing approximately 35 mL of solution with apH of 4.17. (The molar concentration of methanesulfonic acid wasslightly greater than the molar concentration of the compound of FormulaIa.)

Example U Water for Injection; 10 mg/mL Compound of Formula Ia

A 10 mg/mL solution of compound of Formula Ia was prepared by dissolving0.35 grams of the free base of compound of Formula Ia (theoreticalpotency 1000 mg/grams) in 33.91 grams in water for injection to whichwas added 0.87 grams of a 10% methanesulfonic acid solution, providingapproximately 35 mL of solution with a pH of 4.07.

Example V 1.3% Calcium Chloride; 10 mg/mL Compound of Formula Ia

A 10 mg/mL solution of compound of Formula Ia was prepared by adding0.51 grams of the citrate salt of compound of Formula Ia to 34.50 gramsof the 1.3% calcium chloride solution (1.3 grams of calcium chloride wasdissolved in sufficient water for injection to make 100 mL of solution),providing approximately 35 mL of solution with a pH of 3.52.

Example W 10% HPB-CD; 10 mg/mL Compound of Formula Ia

A 10 mg/mL solution of compound of Formula Ia was prepared by dissolving2.88 grams of the citrate salt of compound of Formula Ia in 203.99 gramsof a 10% hydroxypropyl R-cyclodextrin (“HPB-CD”) solution (30.97 gramsof HPB-CD dissolved in sufficient water for injection (213.62 grams) tomake 300 mL of solution). The pH was adjusted by adding 0.44 grams of a10% NaOH (10 grams of NaOH in sufficient water for injection to give 100mL) and 0.066 grams of a 10% HCl solution, providing approximately 202mL of solution with a pH of 4.40.

Example X 10% SBE-CD; 10 mg/mL Compound of Formula Ia

A 10 mg/mL solution of compound of Formula Ia was prepared by dissolving1.45 grams of the citrate salt of compound of Formula Ia in a sufficientamount of a 10% SBE-CD solution (10 grams of SBE-CD dissolved insufficient water to make 100 mL of solution) to provide 100 mL ofsolution.

Example Y 75% Sesame Oil/25% Ethyl Oleate; 10 mg/mL Compound of FormulaIa

A 10 mg/mL solution of compound of Formula Ia in 3:1 (volume/volume)sesame oil:ethyl oleate was prepared by dissolving 0.166 grams of thefree base of compound of Formula Ia (theoretical potency 1000 mg/gram)in 11.87 grams (12.75 mL) of sesame oil and 3.59 grams (4.25 mL) ofethyl oleate, providing approximately 17 mL of solution.

Example Z Miglyol; 10 mg/mL Compound of Formula Ia

A 10 mg/mL solution of compound of Formula Ia in Miglyol 812 wasprepared by dissolving 0.17 grams of the free base of the compound ofFormula Ia (theoretical potency 1000 mg/gram) in 15.90 grams (17 mL) ofMiglyol 812, providing approximately 17 mL of solution.

Example AA 75% Safflower Oil/25% Ethyl Oleate; 10 mg/mL Compound ofFormula Ia

A 10 mg/mL solution of compound of Formula Ia in 3:1 (volume/volume)safflower oil:ethyl oleate was prepared by dissolving 0.177 grams of thefree base of the compound of Formula Ia (theoretical potency 1000mg/gram) in 11.81 grams (12.75 mL) of safflower oil and 3.60 grams (4.25mL) of ethyl, providing approximately 17 mL of solution.

Example BB Micellar; 10 mg/mL Compound of Formula Ia

A 10 mg/mL solution of compound of Formula Ia was prepared by charging aglass vessel with 13.01 grams of water for injection and adding 0.55grams of a 10 molar sodium hydroxide solution (200.04 grams of NaOHdissolved water for injection to a final volume of 500 mL) and 2.21grams of glycocholic acid with stirring until the acid dissolved. Thesolution was heated to 50° C. 4.23 grams of lecithin and 3.75 grams ofan arginine solution (0.752 grams of arginine dissolved in 3.02 grams ofwater for injection) were added and the solution held at 50° C. To thiswas added 0.36 grams of the citrate salt of compound of Formula Ia andthe pH was adjusted by addition of 1.24 grams of a 10% HCl and 0.55grams of a 1 molar sodium hydroxide (20.07 grams of NaOH dissolved inwater for injection for final volume of 500 mL), providing approximately25 mL of solution with a pH of 6.5.

Example CC 12.5% Cremaphor/12.5% Ethanol/75% Saline; 10 mg/mL Compoundof Formula Ia

A 10 mg/mL solution of compound of Formula Ia was prepared by dissolving0.51 grams of the citrate salt of the compound of Formula Ia in 8.75grams of a 50% Cremophor in ethanol solution (50 grams of Cremophor EL(BASF) dissolved in ethanol (dehydrated, 200 proof)) for final volume of100 mL) and 25.50 grams of commercial 0.9% saline, providingapproximately 35 mL of solution with an apparent pH of 4.27.

Example DD 25% Cremaphor/25% Ethanol/50% Saline; 10 mg/mL Compound ofFormula Ia

A 10 mg/mL solution of compound of Formula Ia was prepared by dissolving0.51 grams of the citrate salt of compound of Formula Ia in 17.54 gramsof a 50% Cremophor in ethanol solution and 16.25 grams of commercial0.9% saline, providing approximately 35 mL of solution with an apparentpH of 4.90.

Example EE 40% Ethyl Oleate in Sesame Oil; 10 mg/mL Compound of FormulaIa

A 10 mg/mL solution of compound of Formula Ia was prepared by dissolving0.26 grams of the free base of compound of Formula Ia (theoreticalpotency 1000 mg/g) in 23.26 grams of the 40% ethyl oleate in sesame oilvehicle (20.01 grams of ethyl oleate in 24.72 grams sesame oil to make50 mL), providing approximately 25 mL of solution.

Example FF 5% SBE-CD/1 % Sodium Acetate; 10 mg/mL Compound of Formula Ia

A 10 mg/mL solution of compound of Formula Ia was prepared by dissolving0.43 grams of the citrate salt of compound of Formula Ia in 29.90 gramsof a 1% sodium acetate/5% SBE-CD solution (1 grams of sodium acetate and5 grams of the sodium salt of SBE CD dissolved in water for injectionfor a final volume of 100 mL), providing approximately 30 mL of solutionwith a pH of 5.18.

Example GG 5% SBE-CD/25% PG; 10 mg/mL Compound of Formula Ia

A 10 mg/mL solution of compound of Formula Ia was prepared by dissolving0.43 grams of the citrate salt of compound of Formula Ia in 30.70 gramsof a 5% SBE-CD/25% PG solution (5 grams of the sodium salt of SBE-CD and25 grams of PG dissolved in water for injection for a final volume of100 mL), providing approximately 30 mL of solution with an apparent pHof 4.53.

Example HH 5% SBE-CD/25% NMP: 10 mg/mL Compound of Formula Ia

A 10 mg/mL solution of compound of Formula Ia was prepared by dissolving0.362 grams of the citrate salt of the compound of Formula Ia in 25.82grams of a 25% of N-methylpyrrolidone/5% SBE-CD solution (2.52 grams ofthe sodium salt of SBE-CD and 12.50 grams of N-methylpyrrolidone(“NMP”)(Acros) dissolved in water for injection (36.57 g) for a finalvolume of 50 mL), providing approximately 25 mL of solution with anapparent pH of 4.73.

Example II 50% Ethyl Oleate in Sesame Oil; 10 mg/mL Compound of FormulaIa

A 10 mg/mL solution of compound of Formula Ia was prepared by dissolving0.259 grams of the free base of compound of Formula Ia (theoreticalpotency 1000 mg/g) in 23.04 grams of a 50% ethyl oleate in sesame oilvehicle (25.02 grams of ethyl oleate dispersed in 19.47 grams sesame oilfor a final volume of 50 mL), providing approximately 25 mL of solution.

Example JJ 10% SBE-CD/25% PG; 10 mg/mL Compound of Formula Ia

A 10 mg/mL solution of compound of Formula Ia was prepared by dissolving0.43 grams of the citrate salt of compound of Formula Ia in 31.16 gramsof a 10% SBE-CD/25% PG solution (10 grams of the sodium salt of SBE CDand 25 grams of PG dissolved in water for injection for a final volumeof 100 mL), providing approximately 30 mL of solution with an apparentpH of 4.47.

Example KK 10% SBE-CD; 10 mg/mL Compound of Formula Ia

A 10 mg/mL solution of compound of Formula Ia was prepared by dissolving0.38 grams of the malate salt of compound of Formula Ia (theoreticalpotency 780 mg/gram) in 30.70 grams of a 10% SBE-CD solution, providingapproximately 30 mL of solution with a pH 4.55.

Example LL 10% SBE-CD: 10 mg/mL Compound of Formula Ia

A 10 mg/mL solution of compound of Formula Ia was prepared by dissolving0.434 grams of the citrate salt of compound of Formula Ia in 31.25 gramsof a 10% SBE-CD solution. The pH was adjusted by adding 0.38 grams of10% HCl and 0.04 grams of 10% NaOH, providing approximately 30 mL ofsolution with a pH of 3.02.

Example MM 7.5% SBE-CD; 10 mg/mL Compound of Formula Ia

A 10 mg/mL solution of the citrate salt of the compound of Formula Iacontaining 7.5% SBE-CD was prepared as follows. Water for injection(13175 g) was charged into a glass-lined carboy. The water was heated to30-40° C. and maintained in this temperature range during compounding.SBE-CD (1313 g) was added to the carboy and stirred until dissolved. Thecitrate salt of the compound of Formula Ia (252 g) was added to thecarboy and stirred until dissolved. An additional portion of water forinjection (3295 g) was added to the carboy and stirred until dispersed.The solution was cooled to 20-30° C., producing approximately 17500 mLof solution containing 10 mg/mL of the compound of Formula Ia and 7.5%(weight/volume) SBE-CD with a pH of 4.4.

The resulting solution was filtered through redundant Millipore 0.2micron KVGL04TC3 sterilizing filters into a sterilized glass-linedreceiving tank. A portion of the solution was filled into 20 mL amberglass vials in an aseptic processing area. The vial headspace wasflushed with filtered nitrogen, and the vials were closed and sealedwith rubber stoppers and aluminum crimps. The vials were placed in anautoclave and heated to 121° C., held at that temperature forapproximately 15 minutes, and cooled to room temperature.

The above-described formulations were subcutaneously injected asdescribed above. Table 2 compiles the formulation descriptions and meaninjection site toleration scores. TABLE 2 Formulation Details And MeanInjection Site Toleration Scores Compound of Mean IST Scores Form. IConc. Pain on Size Skin Size Pain on Vehicle Example (mg/mL) # days #sites Injection Erythema (cm²) Thickening (cm²) Palpation Edema 1%Sodium A 10 4 1 0.5 0.3 1.3 1.5 5.2 0 0.1 Chloride 1% Calcium B 10 4 10.2 0 0 1.0 3.5 0.1 0.3 Chloride 1% Sodium C 10 4 1 0.8 0.1 0.3 1.6 6.70.2 0.3 Acetate 40% Glycerol D 10 4 1 0.3 0.3 0.9 1.4 6.7 0.1 0.5 Formal25% 2- E 10 4 1 0.2 0 0 1.9 7.7 0.1 0.3 pyrrolidone 1% Calcium F 5 3 10.1 0 0 0.8 5.3 0 0 Chloride 1% Calcium G 10 4 4 0.3 0 0 0.9 3.7 0 0Chloride 40% Glycerol H 5 3 1 0.5 0 0 1.4 9.0 0 0.4 Formal 40% GlycerolI 10 4 4 0.6 0 0 0.8 2.9 0 0.1 Formal 20% SBE J 10 4 1 0.1 0 0 0 0 0 0Cyclodextrin 20% SBE J 10 4 1 0 0 0 0 0 0 0 Cyclodextrin 1% Calcium K 101 1 0 0 0 0.8 1.6 0 0.1 Chloride pH 5.0 1% Calcium K 10 3 1 0 0 0 1.65.4 0 0.3 Chloride pH 5.0 1% Calcium L 10 1 1 0 0 0 0.7 1.3 0 0 ChloridepH 3.8 1% Calcium L 10 3 1 0 0 0 1.5 6.3 0 0.1 Chloride pH 3.8 40%Glycerol M 10 1 1 0.8 0 0 0.5 1.2 0 0 Formal, Phosphate Buffer pH 3.040% Glycerol M 10 3 1 0.3 0 0 1.3 5.9 0 0.4 Formal pH 3.0 25% NMP N 10 11 1.5 0 0 0.3 0.7 0 0 pH 4.6 25% NMP N 10 3 1 0 0.2 0.3 1.3 4.9 0 0 pH4.6 1% Calcium O 10 1 1 0 0 0 0.8 2.8 0 0 Chloride pH 4.1 1% Calcium O10 3 1 0.2 0 0 1.6 6.6 0 0.1 Chloride pH 4.1 5% SBE P 10 1 1 1.0 0 0 0 00 0 Cyclodextrin pH 4.5 5% SBE P 10 4 1 0.1 0 0 0 0 0 0 Cyclodextrin pH4.5 1% Calcium Q 10 1 1 0.3 0 0 0 0 0 0 Chloride/ 5% SBE -CD 1% CalciumQ 10 4 1 0 0 0 0 0 0 0 Chloride/ 5% SBE-CD 30% PEG- R 10 1 1 1.0 0 0 0.40.5 0 0 400 30% PEG- R 10 3 1 0.3 0 0 1.6 3.4 0 0.3 400 30% PG S 10 1 11.5 0 0 0.4 0.8 0 0 30% PG S 10 3 1 0.3 0 0 2.3 5.1 0 0 1% Calcium T 101 1 0 0.5 0.9 1.1 2.7 0 0 Chloride 1% Calcium T 10 3 1 0.2 0.7 1.8 2.05.8 0 0 Chloride Water for U 10 1 1 0.8 0 0 0.8 1.1 0 0 injection Waterfor U 10 3 1 0.3 0.6 2.0 2.7 6.2 0 0 injection 1.3% Calcium V 10 1 1 0.30 0 1.3 2.3 0 0 Chloride (isotonic) 1.3% Calcium V 10 3 1 0.2 0 0 2.46.5 0 0.1 Chloride (isotonic) 10% HPB- W 10 1 1 0.5 0 0 0.1 0.1 0 0 CD10% HPB-CD W 10 4 1 0.1 0 0 0.1 0.3 0 0 10% SBE-CD X 10 1 1 0 0 0 0 0 00 10% SBE-CD X 10 4 1 0 0 0 0 0 0 0 75% Sesame Y 10 4 1 0.2 0 0 1.0 3.10 0.3 oil/25% Ethyl Oleate Miglyol 812 Z 10 3 1 0.3 0 0 2.7 21 0.2 1.575% Safflower AA 10 3 1 0.1 0 0 1.9 12 0 0.9 Oil/25% Ethyl OleateMicellar BB 10 4 1 0 0 0 1.1 2.5 0 0 12.5% CC 10 4 1 1.0 0 0 1.5 3.3 0.40 cremaphor, 12.5% ethanol, 75% saline 25% DD 10 4 1 0 0 0 1.3 2.7 0 0cremaphor, 25% ethanol, 50% saline 40% Ethyl EE 10 4 1 0 0 0 1.4 1.4 00.1 Oleate in Sesame Oil 5% SBE-CD, FF 10 4 1 0.1 0 0 0.3 0.5 0 0 1%sodium acetate 5% SBE-CD, GG 10 4 1 0 0 0 0.9 2.3 0 0 25% PG 5% SBE -CD,HH 10 4 1 0.6 0 0 1.8 3.8 0 0 25% NMP 50% Ethyl II 10 4 1 0.1 0 0 0.61.3 0 0 Oleate in Sesame oil 10% SBE- JJ 10 4 1 0.3 0 0 0.8 0.8 0 0 CD,25% PG 10% SBE-CD KK 10 4 1 0 0 0 0.1 0.1 0 0 10% SBE-CD LL 10 4 1 0.1 00 0 0 0 0

Preferred Embodiments

1. A pharmaceutical composition with an improved injection sitetoleration comprising a therapeutically effective amount of a neurokininreceptor (NK-1) antagonist with a pharmaceutically acceptablecyclodextrin.

2. A pharmaceutical composition according to preferred embodiment 1wherein the antagonist is selected from the group consisting ofpiperazine compounds, spiro-substituted azacycles, dialkyline piperadinocompounds, trypthophan urea, polycyclic amine compounds, substitutedarylaliphatic compounds, aromatic amine compounds, quaternary ammoniumsalts or aromatic amine compounds, aryl-substituted heterocycles,polycyclicamine compounds, substituted aryl piperazines, carboxamidederivatives, and bis-piperadinyl non-peptidal compounds, or saltsthereof.

3. The pharmaceutical composition of Preferred embodiment 1 wherein theNK-1 antagonist, is a compound of Formula I,

or pharmaceutically acceptable salt or prodrug thereof, wherein R² isselected from the group consisting of methyl, ethyl, isopropyl,sec-butyl and tert-butyl with a pharmaceutically acceptablecyclodextrin.

4. A pharmaceutical composition according to preferred embodiment 3wherein the compound of Formula I is a compound of Formula Ia,

or a pharmaceutically acceptable salt or prodrug thereof.

5. The pharmaceutical composition according to Preferred embodiments 1,2, 3 or 4 wherein the cyclodextrin is selected from β-cyclodextrin,hydroxypropyl β-cyclodextrin, sulfobutylether β-cyclodextrin orsubstituted cyclodextrins.

6. The pharmaceutical composition according to Preferred embodiment 5wherein the cyclodextrin is about 2% to about 40% of the composition.

7. The pharmaceutical composition according to Preferred embodiment 6wherein the cyclodextrin is about 4% to about 20% of the composition.

8. A pharmaceutical composition according to Preferred embodiment 7wherein the cyclodextrin is about 5% to about 10% of the composition.

9. A pharmaceutical composition according to Preferred embodiment 8wherein the cyclodextrin is sulfobutylether β-cyclodextrin orhydroxypropyl β-cyclodextrin.

10. A pharmaceutical composition according to Preferred embodiment 9wherein the therapeutically effective amount of the NK-1 antagonist is0.01 mg/kg to 100 mg/kg of a patient's body weight.

11. A pharmaceutical composition according to Preferred embodiment 10wherein the therapeutically effective amount is 0.10 mg/kg to 10 mg/kgof a patient's body weight.

12. The pharmaceutical composition according to Preferred embodiment 11wherein the pharmaceutically acceptable salt is citrate.

13. A method for the treatment of emesis or improving anesthesiarecovery in a mammal comprising parenterally injecting into the mammal asolution comprising the pharmaceutical composition according toPreferred embodiment 5 in a therapeutically effective amount sufficientfor treating emesis or improving anesthesia recovery, the cyclodextrinbeing present in amounts that are sufficient for improving injectiontoleration at the injection site.

14. The method according to Preferred embodiment 13 wherein thecyclodextrin is about 2% to about 40% of the composition.

15. The method according to Preferred embodiment 14 wherein thecyclodextrin is about 4% to about 20% of the composition.

16. The method according to Preferred embodiment 15 wherein thecyclodextrin is about 5% to about 10% of the composition.

17. The method according to Preferred embodiment 16 wherein thecyclodextrin is sulfobutylether β-cyclodextrin or hydroxypropylβ-cyclodextrin.

18. The method according to Preferred embodiment 17 wherein thetherapeutically effective amount of the NK-1 antagonist is 0.01 mg/kg to100 mg/kg of a patient's body weight.

19. The method according to Preferred embodiment 18 wherein thetherapeutically effective amount is 0.10 mg/kg to 10 mg/kg of apatient's body weight.

20. The method according to Preferred embodiment 19 wherein thepharmaceutically acceptable salt is citrate.

21. A method for improving injection site toleration during thetreatment of emesis or improving anesthesia recovery in a mammalcomprising parenterally injecting into the mammal an aqueouspharmaceutical solution of the pharmaceutical composition according toPreferred embodiment 5.

22. The method according to Preferred embodiment 21 wherein thecyclodextrin is about 2% to about 40% of the composition.

23. The method according to Preferred embodiment 22 wherein thecyclodextrin is about 4% to about 20% of the composition.

24. The method according to Preferred embodiment 23 wherein thecyclodextrin is about 5% to about 10% of the composition.

25. The method according to Preferred embodiment 24 wherein thecyclodextrin is sulfobutylether β-cyclodextrin or hydroxypropylβ-cyclodextrin.

26. The method according to Preferred embodiment 25 wherein thetherapeutically effective amount of the NK-1 antagonist is 0.01 mg/kg to100 mg/kg of a patient's body weight.

27. The method according to Preferred embodiment 26 wherein thetherapeutically effective amount is 0.10 mg/kg to 10 mg/kg of apatient's body weight.

28. The method according to preferred embodiment 27 wherein thepharmaceutically acceptable salt is citrate.

1.-10. (canceled)
 11. A pharmaceutical composition with an improved injection site toleration comprising a therapeutically effective amount of a neurokinin receptor (NK-1) antagonist with a pharmaceutically acceptable cyclodextrin.
 12. A pharmaceutical composition according to claim 11 wherein the antagonist is selected from the group consisting of piperazine compounds, spiro-substituted azacycles, dialkyline piperadino compounds, trypthophan urea, polycyclic amine compounds, substituted arylaliphatic compounds, aromatic amine compounds, quaternary ammonium salts or aromatic amine compounds, aryl-substituted heterocycles, polycyclicamine compounds, substituted aryl piperazines, carboxamide derivatives, and bis-piperadinyl non-peptidal compounds, or salts thereof.
 13. The pharmaceutical composition of claim 12 wherein the NK-1 antagonist is a compound comprising Formula I,

or pharmaceutically acceptable salt or prodrug thereof, wherein R² is selected from the group consisting of methyl, ethyl, isopropyl, sec-butyl and tert-butyl.
 14. A pharmaceutical composition according to claim 13 wherein the compound comprising Formula I is a compound comprising Formula Ia,

or a pharmaceutically acceptable salt or prodrug thereof.
 15. A pharmaceutical composition according to claim 13 wherein the therapeutically effective amount of the NK-1 antagonist is 0.01 mg/kg to 100 mg/kg of a patient's body weight.
 16. A pharmaceutical composition according to claim 14 wherein the therapeutically effective amount of the NK-1 antagonist is 0.01 mg/kg to 100 mg/kg of a patient's body weight.
 17. A pharmaceutical composition according claim 15 wherein the therapeutically effective amount of the NK-1 antagonist is 0.10 mg/kg to 10 mg/kg of a patient's body weight.
 18. A pharmaceutical composition according claim 16 wherein the therapeutically effective amount of the NK-1 antagonist is 0.10 mg/kg to 10 mg/kg of a patient's body weight.
 19. The pharmaceutical composition according to claim 12 wherein said cyclodextrin is selected from β-cyclodextrin, sulfobutylether cyclodextrin, hydroxypropyl cyclodextrin, hydroxyethyl cyclodextrin, glucosyl cyclodextrin, maltosyl cyclodextrin, hydroxypropyl-β-cyclodextrin, sulfobutylether-β-cyclodextrin, hydroxyethyl-β-cyclodextrin, hydroxypropyl-γ-cyclodextrin, hydroxyethyl-β-cyclodextrin, dihydroxypropyl-β-cyclodextrin, glucosyl-β-cyclodextrin, diglycosyl-β-cyclodextrin, maltosyl-β-cyclodextrin, maltosyl-γ-cyclodextrin, maltotrialsyl-β-cyclodextrin, maltotrialsyl-γ-cyclodextrin, dimaltosyl-β-cyclodextrin, cyclodextrin derivatives, various mixtures of cyclodextrin derivatives thereof, mixtures such as maltosyl-β-cyclodextrin/dimaltosyl-β-cyclodextrin, and any other similar cyclodextrin known to those of skill in the art.
 20. The pharmaceutical composition according to claim 19 wherein the cyclodextrin is selected from β-cyclodextrin, hydroxypropyl β-cyclodextrin, sulfobutylether β-cyclodextrin or substituted cyclodextrins.
 21. The pharmaceutical composition according to claim 20 wherein the cyclodextrin is about 2% to about 40% of the composition.
 22. The pharmaceutical composition according to claim 21 wherein the cyclodextrin is about 4% to about 20% of the composition.
 23. The pharmaceutical composition according to claim 22 wherein the cyclodextrin is about 5% to about 10% of the composition.
 24. The pharmaceutical composition according to claim 20 for use as a medicament.
 25. The pharmaceutical composition of (2S,3S)-2-benzhydryl-N-(5-tert-butyl-2-methoxybenzyl)quinuclidin-3-amine and a pharmaceutically acceptable cyclodextrin where said cyclodextrin is selected from the group consisting of β-cyclodextrin, hydroxypropyl β-cyclodextrin, sulfobutylether β-cyclodextrin or substituted cyclodextrins.
 26. The use of a composition according to claim 11 in the manufacture of a medicament for the treatment of a disease for which a NK-1 antagonist is indicated.
 27. A method for the treatment of a disease for which a NK-1 antagonist is indicated in mammals comprising administering to said mammal a therapeutically effective amount of a pharmaceutical composition of claim
 11. 